Published online February 1, 2007
PEDIATRICS Vol. 119 No. 2 February 2007, pp. 419-420 (doi:10.1542/peds.2006-3449)

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LETTER TO THE EDITOR

Acetaminophen Protein Adducts in Children With Acute Liver Failure of Indeterminate Cause: In Reply

Laura P. James, MD
Departments of Pediatrics and Pharmacology
University of Arkansas for Medical Sciences and Arkansas Children's Hospital Research Institute
Little Rock, AR 72202

Jack A. Hinson, PhD
Department of Pharmacology
University of Arkansas for Medical Sciences
Little Rock, AR 72202

Estella M. Alonso, MD
Department of Pediatrics
Siragusa Transplant Center
Children's Memorial Hospital and Northwestern University Feinberg School of Medicine
Chicago, IL 60614

Linda S. Hynan, PhD
Departments of Clinical Sciences and Psychiatry

William M. Lee, MD
Clinical Center for Liver Disease
University of Texas Southwestern Medical Center at Dallas
Dallas, TX 75390-8887

Timothy J. Davern, MD
Department of Internal Medicine
Division of Gastroenterology
University of California
San Francisco, CA 94143-0538

Robert H. Squires, MD
Division of Pediatric Gastroenterology
Children's Hospital of Pittsburgh
Pittsburgh, PA 15213

and the Pediatric Acute Liver Failure Study Group (NIDDK 072146) We read with interest the comments of Dr Bond regarding our recent publication¹ in Pediatrics. We offer the following responses to the points that he raised.

1. Dr Bond noted that there was really no significant difference between the proportion of patients with liver failure of unknown etiology that tested positive for acetaminophen protein adducts (8 of 64) and that of patients with other causes of liver failure that tested positive for acetaminophen protein adducts (3 of 30). Therefore, he concluded that the findings were spurious. Unfortunately, his argument indicates that he ignored the adduct data presented in our Fig 1, which showed the median and range of values for patients with known acetaminophen toxicity, patients with acute liver failure of unknown etiology, and patients with other diagnosed causes of acute liver failure. Although the graph showed that the levels differed between the 3 groups, it is difficult to draw conclusions from the patients with liver failure of other etiologies because the numbers were small. One goal of our study was to establish that levels would be significantly elevated for those with known acetaminophen poisoning, and this was shown. Ongoing studies will help to define the level of sensitivity of the assay and examine adducts in children with various degrees of liver injury after acetaminophen overdose.
   
2. Closely related to Dr Bond's first point, he raises the interesting question of whether acetaminophen protein adducts may be formed in patients who have severe liver dysfunction and receive therapeutic doses of acetaminophen. In patients with depletion in hepatic glutathione content secondary to other disease processes, it is quite possible that this may occur. Recent data in healthy adult volunteers showed that up to 40% of subjects had significant elevation of hepatic transaminases while receiving acetaminophen at therapeutic doses.² Carefully designed prospective studies are necessary to fully address the issue of possible adduct formation and its magnitude in children and adults with preexisting liver injury and subsequent exposure to the recommended doses of acetaminophen.
   
3. Dr Bond also questioned whether the test for acetaminophen protein adducts should be considered to be the "gold-standard" test for acetaminophen toxicity. In 2004, the National Institutes of Health (NIH) called for the development of new laboratory assays for the diagnosis of acetaminophen toxicity (NIH Action Plan), recognizing the limitation of the currently available assay. A multitude of studies conducted in laboratory animals since the 1970s support the concept of acetaminophen protein adducts as the biomarker of acetaminophen liver injury in laboratory animals, and available data suggest that it is mechanistically important in development of the toxicity.^3–6 Previous studies in humans,^7–10 in addition to our recent findings,^1,11 support determination of acetaminophen protein adducts in the evaluation of patients with acetaminophen overdose. As with any new assay, its role in clinical medicine will require repeated testing, refinement, peer review, and interpretation in a variety of clinical settings.
   

REFERENCES

1. James LP, Alonso EM, Hynan LS, et al. Detection of acetaminophen protein adducts in children with acute liver failure of indeterminate cause. Pediatrics. 2006;118(3) . Available at: www.pediatrics.org/cgi/content/full/118/3/e676
2. Watkins PB, Kaplowitz N, Slattery JT, et al. Aminotransferase elevations in healthy adults receiving 4 grams of acetaminophen daily: a randomized controlled trial. JAMA. 2006;296 :87 –93[Abstract/Free Full Text]
3. Jollow DJ, Mitchell JR, Potter WZ, Davis DC, Gillette JR, Brodie BB. Acetaminophen-induced hepatic necrosis. II. Role of covalent binding in vivo. J Pharmacol Exp Ther. 1973;187 :195 –202[Abstract/Free Full Text]
4. Mitchell JR, Thorgeirsson SS, Potter WZ, Jollow DJ, Keiser H. Acetaminophen-induced hepatic injury: protective role of glutathione in man and rational for therapy. Clin Pharmacol Ther. 1974;16 :676 –684[Web of Science][Medline]
5. Pumford NR, Hinson JA, Benson RW, Roberts DW. Immunoblot analysis of protein containing 3-(cystein-S-yl)acetaminophen adducts in serum and subcellular liver fractions from acetaminophen-treated mice. Toxicol Appl Pharmacol. 1990;104 :521 –532[CrossRef][Web of Science][Medline]
6. Roberts DW, Bucci TJ, Benson RW, et al. Immunohistochemical localization and quantification of the 3-(cystein-S-yl)-acetaminophen protein adduct in acetaminophen hepatotoxicity. Am J Pathol. 1991;138 :359 –371[Abstract]
7. Hinson JA, Roberts DW, Benson RW, Dalhoff K, Loft S, Poulsen HE. Mechanism of paracetamol toxicity. Lancet. 1990;335 :732[Web of Science][Medline]
8. Webster PA, Roberts DW, Benson RW, Kearns LF. Acetaminophen toxicity in children: diagnostic confirmation using a specific antigenic biomarker. J Clin Pharmacol. 1996;36 :397 –402[Abstract]
9. Muldrew KL, James LP, Coop L, et al. Determination of acetaminophen-protein adducts in mouse liver and serum and human serum after hepatotoxic doses of acetaminophen using high-performance liquid chromatography with electrochemical detection. Drug Metab Dispos. 2002;30 :446 –451[Abstract/Free Full Text]
10. James LP, Farrar HC, Sullivan JE, et al. Measurement of acetaminophen-protein adducts in children and adolescents with acetaminophen overdoses. Pediatric Pharmacology Research Unit Network, NICHD. J Clin Pharmacol. 2001;41 :846 –851[Abstract]
11. Davern TJ 2nd, James LP, Hinson JA, et al. Measurement of serum acetaminophen-protein adducts in patients with acute liver failure [published correction appears in Gastroenterology. 2006;130:1933]. Gastroenterology. 2006;130 :687 –694[CrossRef][Web of Science][Medline]

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PEDIATRICS (ISSN 1098-4275). ©2007 by the American Academy of Pediatrics

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This Article Extract Full Text (PDF) Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services E-mail this article to a friend Similar articles in this journal Alert me to new issues of the journal Add to My File Cabinet Download to citation manager Request Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by James, L. P. Search for Related Content PubMed Articles by James, L. P. Related Collections Gastrointestinal Tract Social Bookmarking                         What's this?